Gaspar Ludovit, Reich Michal, Kassai Zoltan, Macasek Fedor, Rodrigo Luis, Kruzliak Peter, Kovac Peter
BIONT, a.s.Bratislava, Slovak Republic; 2nd Department of Internal Medicine, Faculty of Medicine, Comenius University and University HospitalBratislava, Slovak Republic.
BIONT, a.s. Bratislava, Slovak Republic.
Am J Nucl Med Mol Imaging. 2016 Jul 6;6(3):154-65. eCollection 2016.
Nine years of experience with 2286 commercial synthesis allowed us to deliver comprehensive information on the quality of (18)F-FDG production. Semi-automated FDG production line using Cyclone 18/9 machine (IBA Belgium), TRACERLab MXFDG synthesiser (GE Health, USA) using alkalic hydrolysis, grade "A" isolator with dispensing robotic unit (Tema Sinergie, Italy), and automatic control system under GAMP5 (minus2, Slovakia) was assessed by TQM tools as highly reliable aseptic production line, fully compliant with Good Manufacturing Practice and just-in-time delivery of FDG radiopharmaceutical. Fluoride-18 is received in steady yield and of very high radioactive purity. Synthesis yields exhibited high variance connected probably with quality of disposable cassettes and chemicals sets. Most performance non-conformities within the manufacturing cycle occur at mechanical nodes of dispensing unit. The long-term monitoring of 2286 commercial synthesis indicated high reliability of automatic synthesizers. Shewhart chart and ANOVA analysis showed that minor non-compliances occurred were mostly caused by the declinations of less experienced staff from standard operation procedures, and also by quality of automatic cassettes. Only 15 syntheses were found unfinished and in 4 cases the product was out-of-specification of European Pharmacopoeia. Most vulnerable step of manufacturing was dispensing and filling in grade "A" isolator. Its cleanliness and sterility was fully controlled under the investigated period by applying hydrogen peroxide vapours (VHP). Our experience with quality assurance in the production of [(18)F]-fluorodeoxyglucose (FDG) at production facility of BIONT based on TRACERlab MXFDG production module can be used for bench-marking of the emerging manufacturing and automated manufacturing systems.
2286次商业合成的九年经验使我们能够提供有关（18）F-FDG生产质量的全面信息。使用Cyclone 18/9机器（比利时IBA）的半自动FDG生产线、采用碱水解的TRACERLab MXFDG合成器（美国通用电气医疗集团）、配备分配机器人单元的“A”级隔离器（意大利Tema Sinergie）以及符合GAMP5标准的自动控制系统（斯洛伐克minus2），通过全面质量管理工具评估为高度可靠的无菌生产线，完全符合药品生产质量管理规范以及FDG放射性药物的即时交付要求。氟-18的接收产量稳定且放射性纯度极高。合成产率表现出较大差异，这可能与一次性盒式装置和化学试剂套装的质量有关。制造周期内的大多数性能不符合情况发生在分配单元的机械节点处。对2286次商业合成的长期监测表明自动合成器具有很高的可靠性。休哈特控制图和方差分析表明，出现的轻微不符合情况大多是由于经验不足的工作人员偏离标准操作程序以及自动盒式装置的质量问题所致。仅发现15次合成未完成，4例产品不符合欧洲药典标准。制造过程中最脆弱的步骤是在“A”级隔离器中的分配和灌装。在研究期间，通过应用过氧化氢蒸汽（VHP）对其清洁度和无菌性进行了全面控制。我们在基于TRACERlab MXFDG生产模块的BIONT生产设施中生产[（18）F]-氟脱氧葡萄糖（FDG）的质量保证经验可用于新兴制造和自动化制造系统的基准测试。
